DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s election without traverse of group I, claims 1-11 and 15-20, in the reply filed on 12/9/25 is acknowledged. Applicant has further elected an IL-2Rb transmembrane linking juxtamembrane domain, a CAR construct configuration of TAA scFV-CD8Hinge-IL2Rb tm jm DT-4-1BB-CD3zeta, with scFV binding to CEA. Applicant elects SEQ ID NO: 1 as TM, SEQ ID NO: 4 as juxtamembrane, SEQ ID NO: 27 as TM linking JM, SEQ ID NO: 5 as CEA scFV, SEQ ID NO: 46 as leader sequence, and P2A of SEQ ID NO: 43. Claims 12-14 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention. Claims 5 and 8 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to non-elected species. It is noted that claim 4 is included in the examination to the extent that the limitation that the IL2Rb degradation sequence is C-terminal of the cytoplasmic region is recited as a preferred embodiment, which is being interpreted as an optional. Therefore, the claim reads on the elected construct wherein DT (i.e. degradation sequence) is N-terminal to the cytoplasmic sequence. Claims 1-4, 6-7, 9-11, and 15-20 are being acted upon.
Claim interpretation
The claims recite limitations of a CAR comprising from N to C terminal certain configurations, for example, HA-MN14op CEA scFv-CD8Hinge-IL2Rb tm jm DT-4-1BB-CD3z (see claims 2-3, for example). The claim is directed to a CAR “comprising” the recited elements in N to C- terminal, which is open term that does not exclude unrecited elements. Therefore, the scope of the claim construct would encompass other elements in between the recited elements. For example, HA-MN14op CEA scFv-CD8Hinge-IL2Rb tm jm DT-IL-2Rb-4-1BB--CD3zeta, wherein IL-2Rb represents intracellular signaling domain, would be within the scope of claim 3, since the required elements are still arranged in the N-terminal to C-terminal order specified in the claim, with additional elements being added. MN14op CEA scFV is being interpreted as encompassing an scFV derived from MN14 anti-CEA antibody.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-4, 6-7, 9-11, and 15-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is indefinite in the recitation of IL2Rb “juxtamembrane domain”. The scope of the claims is unclear and indefinite. The specification does not define the term, and it is unclear what specific sequences would be encompassed. For example, would an extracellular portion of IL-2R immediately adjacent to the transmembrane domain be within the scope of a “juxtamembrane domain”, since it is near the membrane sequence? Likewise, the dependent claims, such as claims 2-3 and 7, refer to specific constructs such as HA-MN14op CEA scFv-CD8Hinge-IL2Rb tm jm DT-4-1BB-CD3z. It is not clear what specific sequences are required in, for example, the recitation of “4-1BB”. Would it require an intracellular signaling domain of 4-1BB, or could it be any domain from 4-1BB. Likewise, the recitation of, for example, MN14op is unclear and indefinite, and the specification does not define the term. For the purposes of applying prior art, MN14op CEA scFV is being interpreted as encompass any scFV derived from MN14 anti-CEA antibody.
Regarding claims 2-4 and 7 the phrase "preferably” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For the purposes of examination, the limitations following the phrase preferably are not being interpreted as required elements of the claim, but are optional.
Claims 4 and 18 recite that the IL2Rb degradation sequence comprises an amino acid sequence at least 95%-100% identical to SEQ ID NOs: 2. SEQ ID NO: 2 is 8 amino acids in length, and even a single substitution would result in less than 95% identity. Therefore, it is unclear what could be modified in SEQ ID NO: 2 to meet the limitation “at least 95% identity”. Claim 6-7 are indefinite for the same reasons in the recitation of a sequence having at least 95% identity to SEQ ID NO: 4, 39 or SEQ ID NO: 44 which are too short to allow for any changes.
Claim 6 recites the limitation "the MN14op CEA scFV… or leader sequence" and “the P2A” in the last 6 lines of the claim. There is insufficient antecedent basis for these limitations in the claim.
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 2-3, 6, are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. Specifically, there is insufficient written description to demonstrate that applicant was in possession of the claimed genus of “MN14opCEA scFV” or sequences having at least 95% identity thereto.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See MPEP 2163.
The claims encompass a genus of MN14opCEA scFV, which would include a genus of antibody variants derived from MN14. Likewise, the claims recite that the scFV has at least 95% identity to the scFV of SEQ ID NO:5 or to the CAR comprising SEQ ID NO: 9. This would encompass numerous changes and combination of changes in the scFV portion, including in the CDRs.
The state of the art is such that the 6 CDRs of an antibody are critically involved in antigen binding, that even single amino acid changes can alter antigen specificity of binding, and that CDR mutations are unpredictable in terms of affinity, specificity, and solubility, and are also context dependent (see Hall, 1992, and Rabia, 2018). The only species of MN14opCEA scFV disclosed is SEQ ID NO: 5, which is not sufficiently representative of the genus of MN14opCEA scFV encompassed by the instant claims, or sequences 95% identical to SEQ ID NO: 5 or SEQ ID NO: 9.
The instant application has not provided a sufficient description showing possession of the necessary functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus of antibodies and inhibitors encompassing various structures, specificities and functions. Further, the Court has interpreted 35 U.S.C. §112, first paragraph, to require the patent specification to “describe the claimed invention so that one skilled in the art can recognize what is claimed. Enzo Biochem, Inc. v. Gen-Probe Inc, 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002).
In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s “disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 43 USPQ2d 1398 (Fed Cir. 1997)).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Also, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., lnc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Meeting the written description threshold requires showing that the applicant was in “possession” of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning – i.e., what the written description and knowledge in the art would lead one to speculate as to modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also ensures that when a patent claims a genus by function, the specification recites sufficient materials to accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3.
Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 4, 6-7, 9-11, 15-20 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 2018/0312570.
The ‘570 publication teaches a CAR comprising a ligand binding scFV, a spacer, a transmembrane domain, a cytokine receptor endodomain, and an intracellular T cell. signaling domain (See page 2 and 5-6). The ‘570 publication teaches that the cytokine receptor endodomain can be IL-2 receptor b-chain endodomain of SEQ ID NO: 2 and that the intracellular T cell signaling domain may comprise one or more of CD3zeta endodomain and a costimulatory domain such as CD28 or 4-1BB endodomain (see page 2 and 5-6, and 10 in particular). The ‘570 publication teaches that the transmembrane domain can be from IL-2Rb with a sequence of SEQ ID NO: 8 (which is identical to SEQ ID NO: 1 of the instant application, see page 8, in particular). The ‘570 publication teaches that the arrangement of the singling domains is such that the cytokine receptor endodomains are proximal to the membrane (in other words, they comprise an IL-2Rb juxtamembrane domain), and the T cell signaling domains are distal to the membrane, i.e. ordered IL-2Rb endodomain-T cell signaling endodomain (See page 2, in particular). The ‘570 publication teaches dual CAR constructs comprising said CAR and a second CAR comprising a scFV antigen binding domain, a transmembrane domain, and an intracellular signaling domain (see page 4, in particular). The ‘570 publication teaches that the tumor antigen targeted by the antigen binding extracellular scFV can be CEA (See page 9, in particular). Furthermore, the endodomain from IL2-Rb of SEQ ID NO: 2 as taught by the ‘570 application comprises a region next to the membrane, i.e. a juxtamembrane region, and further comprises the IL-2Rb degradation sequence of SEQ ID NO: 2 of the instant application adjacent thereto (see residues 1-19 which would be the “juxtamembrane region” and residues 20-27 which are identical to SEQ ID NO: 2 of the instant application). See also SEQ ID NO: 22 of the ‘570 publication which is an exemplified CAR comprising as scFV, an IL-2Rb transmembrane domain, a region of IL-2Rb endodomain that is immediately adjacent to the transmembrane domain (i.e. an IL-2Rb juxtamembrane domain) and said IL-2Rb degradation sequence (i.e. it comprises a transmembrane linking juxtamembrane domain of IL-2Rb) and an intracellular signaling domain. Said IL-2Rb endodomain comprising the degradation sequence is C-terminal to the transmembrane region (see drawings and SEQ ID NO; 22). The ‘570 publication teaches nucleic acids and vectors encoding said CAR and compositions comprising said CAR (see pages 3-5, in particular).
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-2, 4, 6-7, 9-11, 15-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0312570.
The teachings of the ‘570 publication described above. The ‘570 publication also teaches that the spacer may be a CD8 stalk sequence of SEQ ID NO: 5 (see page 8, in particular). Said CD8 stalk of SEQ ID NO: 5 is identical to the sequence disclosed in the instant specification as a CD8 hinge (compare SEQ ID NO: 5 of the ‘570 publication with the CD8hinge as compared to, for example, SEQ ID NO: 6 of the instant application). The ‘570 publication teaches that the T cell intracellular signaling domain can be ordered costimulatory domain-CD3 (for example, see SEQ ID NO: 13 which is an example using CD28 costimulatory domain, CD3zeta domain, wherein the costimulatory domain is N-terminal to the CD3 domain). Therefore, although not explicitly taught in one single embodiment, it would be obvious to select from the domains specifically disclosed for use in the CAR and to arrange them in the format taught in the reference, i.e. CEA-scFV-CD8stalk/hinge-IL-2RB tm (SEQ ID NO: 8)-IL-2Rb endodomain (SEQ ID NO: 2)-4-1BB-CD3z. Said SEQ ID NO: 8 is identical to the transmembrane domain of SEQ ID NO: 1 of the instant application, and said SEQ ID NO: 2 comprises the degradation sequence of SEQ ID NO: 2 of the instant application. Furthermore, creating the construct wherein IL-2Rb transmembrane (SEQ ID NO: 8) is followed by IL-2Rb endodomain (SEQ ID NO: 2), as obvious above, would provide a sequence of:
IPWLGHLLVGLSGAFGFIILVYLLINCRNTGPWLKKVLKCNTPDPSKFFSQLSSEHGGDVQKWLSSPFPSSSFSPGGLAPEISPLEVLERDKVTQLLLQQDKVPEPASLSSNHSLTSCFTNQGYFFFHLPDALEIEACQVYFTYDPYSEEDPDEGVAGAPTGSSPQPLQPLSGEDDAYCTFPSRDDLLLFSPSLLGGPSPPSTAPGGSGAGEERMPPSLQERVPRDWDPQPLGPPTPGVPDLVDFQPPPELVLREAGEEVPDAGPREGVSFPWSRPPGQGEFRALNARLPLNTDAYLSLQELQGQDPTHLV.
The gray highlighted portion represents transmembrane of SEQ ID NO: 8, and the non-highlighted portion represents endodomain SEQ ID NO: 2 from the ‘570 publication. The bolded portion of the sequence is identical to SEQ ID NO: 27 of the instant application (i.e. IL-2Rb tm jm), and the portion in italics is identical to SEQ ID NO: 2 of the instant application (i.e. DT). Thus, the ‘570 publication makes obvious a construct that comprises in N-terminal to C-terminal order a CEA scFV, a CD8 hinge, an IL-2Rb tm jm DT, 4-1BB, and CD3z, which meets the limitation of claim 2 of the instant application.
Claim 3 is rejected under 35 U.S.C. 103(a) as being unpatentable over 2018/0312570, as applied to claims 1-2 above, and further in view of US20020165360.
The teachings of the ‘570 are described above.
The reference differs from the claimed invention in that it does not explicitly teach MN14opCEA scFV.
The ‘360 publication teaches a humanized VH and VL of anti-CEA MN14 antibody that can be arranged in the form of an scFV for use as an antigen binding domain in chimeric polypeptides for directing T cells to target malignant cells expressing CEA, i.e. for using in a CAR.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use the MN14 scFV of the ‘360 publication, as the CEA-scFV in the CAR constructs of the ‘570 publication. The ordinary artisan at the time the invention was made would have been motivated to do so with a reasonable expectation of success, because it is taught as useful in chimeric polypeptides for directing T cells to target malignant cells expressing CEA, i.e. for using in a CAR.
Furthermore, do so would involve choosing among a finite number of predictable options which could be pursued with a reasonable expectation of success. A person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (see KSR International Co. V. Telefex Inc 82 USPQ2d 1385).
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY E JUEDES whose telephone number is (571)272-4471. The examiner can normally be reached on M-F from 7am to 3pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached on 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644